Alcohol’s Effects on the Adolescent Brain—What Can Be
Learned From Animal Models

Susanne Hiller-Sturmhöfel, Ph.D., and H. Scott Swartzwelder,
Ph.D.

Susanne Hiller-Sturmhöfel, Ph.D., is senior science editor
for

Alcohol Research & Health.

H. Scott Swartzwelder, Ph.D., is a professor in the Department
of Psychiatry and Behavioral Sciences at Duke University Medical Center and
a senior research career scientist at the Durham Veterans Affairs Medical
Center, both positions in Durham, North Carolina.

Because of legal and ethical constraints
on alcohol research in human adolescents, many studies of alcohol’s
effects on the developing brain have been conducted in animal models, primarily
rats and mice. The adolescent brain may be uniquely sensitive to alcohol’s
effects because major changes in brain structure and function occur during
this developmental period. For example, adolescent animals are more sensitive
than adults to the effects on memory and learning that result from alcohol’s
actions on the hippocampus. Conversely, adolescent animals appear to be less
sensitive than adults to alcohol-related motor impairment, alcohol-induced
sedation, and the development of seizures during withdrawal. Alcohol exposure
during adolescence can have long-lasting effects and may interfere with normal
brain functioning during adulthood.

Adolescence and young adulthood are developmental stages of transition
during which humans, as well as members of many other species, mature physically
and behaviorally into their adult state. Adolescents and young adults need
to acquire the physical and behavioral skills that will allow them to live
independently of their parents, sustain themselves, and reproduce. This period
is marked by more frequent and sophisticated social interactions with peers,
exploration of new situations and behaviors, and an increased willingness
to take risks. In humans, this often involves the initiation of alcohol and
other drug use.

At the same time, the brain undergoes considerable structural and
functional changes, at least in part in response to the individual’s
many new experiences. Connections among nerve cells (neurons) in the brain
can change based on which neurons or groups of neurons are regularly stimulated,
a characteristic known as plasticity. This natural process serves to eliminate
unnecessary or unused nerve cell connections,1 allowing the survival
of only those neurons that make meaningful contacts with other neurons. (1
Human infants are born with far more neurons than are found in the adult brain.
Based on a child’s interactions with the environment, the neurons and
connections that are most meaningful can be selected.) This winnowing of neurons
is influenced by, among other factors, the adolescent’s interactions
with and experiences in the outside world.

Adolescence is such a critical phase in brain development that the
actions of alcohol and other drugs on the brain can be assumed to have a particularly
profound impact during this developmental period. Indeed, research has shown
that compared with the adult brain, the adolescent brain is particularly sensitive
to some effects of alcohol, yet more resistant to other effects. Much of this
research, especially investigations of specific effects of acute alcohol administration,
has been conducted in animals because studies involving administration of
alcohol to human adolescents are subject to very stringent regulations, and
certain studies of alcohol’s effects on the adolescent brain can be
conducted only using animal models. This article reviews some of the differences
in alcohol’s effects on the adolescent and adult brain that were identified
using these animal models. The accompanying article by Tapert and colleagues
summarizes information that has been obtained in studies of human adolescents
and young adults.

MAJOR CHANGES IN BRAIN STRUCTURE AND FUNCTION DURING ADOLESCENCE

Adolescence in humans is broadly defined as the second decade of
life, although some researchers consider ages up to 25 years as “late
adolescence.” The corresponding period in laboratory animals that are
frequently used as study subjects is just as loosely defined. In rats it typically
spans postnatal days 30–50 (i.e., PD30–PD50). In both humans and
animal models, adolescence is a period when the brain undergoes extensive
remodeling. New connections among neurons are being formed; at the same time,
a substantial number of existing connections are lost (see Spear 2000). It
is hypothesized that this plasticity allows the individual’s brain to
be sculpted based on his or her personal experiences and interactions with
the outside world (Chugani 1998).

One brain region where particularly extensive remodeling occurs
is the frontal region of the outer layer of the brain—the prefrontal
cortex—which is thought to be involved in working memory, voluntary
motor behavior, impulse control, rule learning, spatial learning, planning,
and decisionmaking (see Spear 2000; White and Swartzwelder 2005). These changes
are especially extensive in humans. Although the number of neurons and neuronal
connections in the prefrontal cortex appear to decline during adolescence,
the relative importance of the frontal lobes increases.

Developmental changes in the behavioral relevance of certain brain
areas are accompanied by increases or decreases in the activities of chemicals
called neurotransmitters, which help transmit nerve signals from one neuron
to another. This signaling takes place when neurotransmitters released by
one neuron bind to protein molecules called receptors on the surface of the
receiving neuron. The interaction between the neurotransmitter and its receptor
initiates chemical and electrical changes in the signal-receiving neuron that
influence the generation of a new nerve signal in that cell. In this way,
nerve cells and circuits communicate and drive behavior. Excitatory neurotransmitters
promote the generation of new nerve signals, whereas inhibitory neurotransmitters
make it more difficult to generate a nerve signal in a signal-receiving neuron.
Numerous neurotransmitters and their receptors have been identified that act
on specific cells or groups of cells and have specific effects on those cells.

Two important neurotransmitter systems that undergo substantial
changes during adolescence and are affected by alcohol consumption are dopamine
and gamma-aminobutyric acid (GABA). Dopamine can have both excitatory and
inhibitory effects, depending on the cells it acts on. Dopamine-releasing
and dopamine-receiving cells are found in numerous brain areas. One prominent
region, which lies deep within the brain, is called the striatum. It consists
of several components that are involved in behaviors such as learning to automatically
execute complex movements triggered by a voluntary command (e.g., driving
a car). Another dopamine-using area is the nucleus accumbens, which plays
a role in learning and performing certain behaviors in response to incentive
stimuli (i.e., motivation) (Di Chiara 1997). Activity in the nucleus accumbens
in part accounts for the fact that people perceive the effects of drinking
alcohol or taking other drugs as pleasurable (Di Chiara 1997).

During adolescence, the dopamine system in the striatum appears
to undergo substantial changes. For example, studies in rats have found that
dopamine receptor levels in the striatum increase during early adolescence
but then decrease during late adolescence and young adulthood (Teicher et
al. 1995). At the same time, dopamine receptor levels in the nucleus accumbens
increase dramatically.

GABA is the primary inhibitory neurotransmitter in the brain—that
is, it represses the activity of other brain cells. Alcohol generally enhances
the effects of GABA on its receptors. This enhanced GABA activation may play
a role in mediating the sedative effects of alcohol and other sedating agents
(Mihic and Harris 1997). In addition, alcohol’s effects on GABA and
its receptors are thought to contribute to the development of tolerance to
and dependence on alcohol (Mihic and Harris 1997). Like dopamine, the GABA
system changes substantially during adolescence. Studies in rats have found
that the number of GABA receptors, and thus the activity of the GABA system,
increases markedly in several brain structures during early adolescence (Moy
et al. 1998).

In addition to these two neurotransmitter systems, a system using
the neurotransmitter glutamate also appears to undergo changes during adolescence.
Glutamate interacts with several receptors, including one called the NMDA
receptor. Evidence from animal studies indicates that the NMDA receptor complex
changes during postnatal development, and these changes may continue into
adolescence (McDonald et al. 1990).

Although it is beyond the scope of this article to review the changes
occurring in various brain structures and neurotransmitter systems in more
detail, this brief description demonstrates that adolescence is a period of
profound alterations in brain function. Therefore, it is reasonable to expect
that alcohol’s effects on the brain and behavior may differ for adolescents
and adults. The following sections will review some of the differences in
sensitivity to alcohol that have been identified using animal models.

ADOLESCENTS ARE MORE SENSITIVE THAN ADULTS TO ALCOHOL’S MEMORY-IMPAIRING
EFFECTS

Alcohol’s
Effects on Memory

Among its many effects on the brain and brain function—such
as impairing balance, motor coordination, and decisionmaking—alcohol
interferes with the drinker’s ability to form memories (i.e., it is
an amnestic agent). However, alcohol does not impair all types of memory equally.
Alcohol disrupts a person’s ability to form new, lasting memories to
a far greater extent than it interferes with the ability to recall previously
established memories or to hold new information in memory for just a few seconds
(see White and Swartzwelder 2004). One study conducted with young adults ages
21 to 29 found that intoxicated study participants could recall items on word
lists immediately after the lists were presented, but they had greater difficulty
recalling the information 20 minutes later (Acheson et al. 1998). Interestingly,
this effect was much more powerful in the younger subjects in this age group—that
is, people in their early twenties. In addition, alcohol particularly affects
the ability to form explicit memories—that is, memories of facts (e.g.,
names and phone numbers) or events (e.g., what the drinker did the previous
night). Because different brain areas play a role in the formation of different
types of memories, this pattern of alcohol-related memory impairment allows
researchers to make assumptions about the brain regions that are most affected
by alcohol. Thus, the pattern of memory impairment observed after intoxication
is similar to that found in patients with damage to a brain area called the
hippocampus.

Alcohol and the Hippocampus

The hippocampus is located deep under the brain’s surface
(see figure 1) but is extensively connected with the outer layer of the brain
(i.e., the neocortex). It consists of only a few layers of cells arranged
in a characteristic shape with several bends and folds. The primary cells
in the hippocampus are called pyramidal cells because of their shape. The
hippocampus can be divided into several areas, and studies in humans have
found that in some patients with an inability to form new explicit memories,
brain damage was limited to a single region of hippocampal neurons called
the CA1 region (Zola-Morgan et al. 1986). In rodents, the activity of CA1
cells correlates strikingly with behavior: Each CA1 neuron tends to emit signals
primarily when the animal is in a specific area of its environment. For example,
cell A may be active predominantly when the animal is in the northeast corner
of its cage, whereas cell B may become active when the animal enters the southwest
corner of the cage. As a result, these cells can play a very strong and specific
role in spatial learning (e.g., the ability to learn the path through a maze
or the location of a certain item, such as a food reward).

Figure 1 Location of the hippocampus, an area of the
brain that appears to be particularly vulnerable to alcohol's effects.
It sits below the surface of the neocortex in the rat brain (left) and
the human brain.

Researchers have used this characteristic of the CA1 cells to assess the
effects of alcohol exposure and other interventions on hippocampal cell
activity in intact, living rodents. In one study, electrodes were implanted
in the hippocampus of rats that then were able to move freely around their
cages. After the animals were administered alcohol, the activities of their
CA1 cells were measured. This study found that the activity of the CA1 cells
was reduced when alcohol levels reached at least 0.5 grams per kilogram
(g/kg) of body weight and ceased almost completely at higher alcohol doses
(White and Best 2000). This finding is consistent with the hypothesis that
alcohol can interfere with the formation of new explicit memories by disrupting
hippocampal function.

Alcohol’s Effects on Long-Term Potentiation

In addition to interfering with the activity of CA1 cells, alcohol can
impair other hippocampal functions. One of these, a process called long-term
potentiation (LTP), is an experimentally induced adaptation of the nerve
cell connections in response to repeated activation or stimulation of these
connections.2 (2 Although there have been some demonstrations
of “LTP-like phenomena” in the brain during certain types of
learning, the term “LTP” itself refers to an experimentally
induced change in brain function.) To illustrate, imagine two neurons in
the hippocampus—a CA1 neuron and a neuron from a region called CA3—that
connect in the hippocampus, with the CA3 neuron sending signals to the CA1
neuron. To transmit the signals, the CA3 neuron releases a neurotransmitter,
which then interacts with receptors on the surface of the CA1 neuron,3
resulting in the formation of a new nerve signal in the CA1 neuron (see
figure 2). (3 In normal brain function, nerve signals during
memory formation are passed from other areas of the cortex to a region known
as dentate gyrus, then to CA3 cells, CA1 cells, and finally back to the
cortex.) The intensity of this signal depends on various factors, including
the number of receptors on the CA1 neuron. When the CA3 neuron first is
exposed to a stimulus, it will emit a signal that leads to a certain level
of response in the CA1 neuron. This is called the baseline response. The
CA3 neuron then can be stimulated experimentally in a specific pattern,
a process that resembles what happens during actual learning events. If
the original stimulus subsequently is reapplied to the CA3 neuron, it will
evoke a response in the CA1 neuron that is substantially greater than the
response that occurred after the initial stimulation (i.e., the response
is potentiated). In other words, as the result of the patterned stimulation,
the CA1 cell becomes more responsive to signals emitted by the CA3 cell.
This potentiated response often persists for a long period of time, hence
the name “long-term” potentiation. There is accumulating evidence
that something like LTP occurs naturally during learning and memory formation.

Figure 2 Schematic representation of the long-term
potentiation (LTP) process. When a hippocampal CA3 cell is initially
stimulated, it releases the neurotransmitter glutamate, which binds
to NMDA receptors on a CA1 cell and induces a response of a certain
size (baseline response). One mechanism underlying the induction of
LTP may be that when the CA3 cell is repeatedly stimulated in the proper
pattern, the number of glutamate receptors on the CA1 cell increases
and the receptors become activated. If the original stimulus is then
reapplied to the CA3 cell, the resulting glutamate release will induce
a much greater response in the CA1 cell. This is called long-term potentiation.

Alcohol has been shown to interfere with LTP during experiments using
hippocampal brain slices from rats. In these experiments, alcohol concentrations
corresponding to those achieved in humans after consuming only one or two
drinks interfered with the establishment of LTP (Blitzer et al. 1990). The
brain slices were kept in a special fluid, and two electrodes were introduced
into the tissue, one that allowed stimulation of the CA3 cells and one that
recorded the responses of the CA1 cells. If sufficient alcohol was present
in the surrounding fluid during the repeated patterned stimulation of the
CA3 cells, LTP was not detected in the CA1 cells— that is, their response
remained at the baseline level. However, adding alcohol to the fluid after
the patterned stimulation had no effect on LTP, which is consistent with
the observation that alcohol consumption does not impair recall of previously
established memories. Although experiments like this make it tempting to
equate LTP with actual learning, it is important to remember that LTP really
is a manifestation of neural plasticity that shares some common mechanisms
with learning. Even though actual learning is certainly more complex than
simple LTP induced in the lab, the LTP process represents an excellent opportunity
to study the brain mechanisms underlying memory and the effects of drugs
such as alcohol on these mechanisms.

One neurotransmitter system involved in the establishment of LTP is the
excitatory neurotransmitter glutamate and its NMDA receptor. When this receptor
is activated by glutamate, it allows calcium to enter the cells. Repeated
calcium influx, in turn, sets off a chain reaction leading to long-lasting
changes in the structure and/or function of the cells that cause LTP. Alcohol
has been shown to interfere with activation of the NMDA receptor, thereby
reducing calcium influx and, thus, the subsequent changes in cell function
that result in LTP. Researchers think that this is the main mechanism through
which alcohol prevents establishment of LTP, although other neurotransmitter
systems also may play a role (see White and Swartzwelder 2004).

Differential Effects of Acute Alcohol on Memory in Adolescents
and Adults

Some evidence suggests that alcohol’s effects on memory and learning
are much more severe in adolescents than in adults. Although difficult to
assess in humans, age differences in alcohol’s effects on memory can
be studied in rodents. One approach uses a test called the Morris water
maze task. In this type of experiment, animals are placed in a large circular
tank filled with opaque water. The animals must then locate a platform,
submerged about an inch beneath the surface, where they can rest. The ability
to remember the location of the platform across repeated trials requires
activity of the hippocampus; thus, changes in hippocampal function can be
detected by measuring the animal’s ability to learn the location of
the platform.

To assess age-dependent effects of alcohol, Markwiese and colleagues (1998)
compared the performance of alcohol-exposed adolescent and adult rats in
the Morris water maze task. Each animal underwent 5 days of training to
learn the location of the platform. Before each training session, one group
of animals received no alcohol, and two other groups received one of two
different alcohol doses. The investigators then compared how long it took
the alcohol-exposed and control animals to remember the location of the
platform. Among the adult animals, only those exposed to the highest alcohol
concentration showed learning impairments compared with the control group.
In contrast, adolescent animals also showed impairments after they had received
the lower alcohol dose (Markwiese et al. 1998). This experiment demonstrates
that adolescent rats are more vulnerable to alcohol’s effects on memory
and learning than are adult rats. It is not known if the same age-related
difference exists in humans, as corresponding experiments in human adolescents
cannot be done for obvious reasons. However, as mentioned previously, one
study comparing people in their early twenties with people in their late
twenties found that the younger age group seemed more vulnerable to alcohol-induced
memory impairment (Acheson et al. 1998).

Researchers also have investigated the mechanisms underlying age-related
differences in sensitivity to alcohol’s effects on memory. These analyses
have demonstrated that alcohol-induced inhibition of LTP and of NMDA receptor-mediated
activity were greater in brain slices from adolescent rats than in brain
slices from adult rats. For example, in studies using hippocampal slices
taken from adolescent and adult rats, repeated stimulation in the absence
of alcohol induced LTP in samples taken from both age groups (Swartzwelder
et al. 1995a; Pyapali et al. 1999). In fact, in the absence of
alcohol, the LTP was more pronounced in adolescent than in adult brain tissue.
When alcohol was added, however, LTP induction was reduced substantially
or almost completely blocked in the adolescent tissue, whereas it took much
higher alcohol concentrations to inhibit the LTP process in tissue from
adults.

Similar experiments compared the activity of the glutamate/NMDA system
in response to stimulation in the presence or absence of alcohol in hippocampal
brain slices from adolescent and adult rats. It took significantly higher
concentrations of alcohol to reduce NMDA receptor activity in the adult
brain slices, compared with those taken from adolescent animals (Swartzwelder
et al. 1995b).4 (4 Greater sensitivity of the glutamate/NMDA
system in adolescents is not limited to the hippocampus but also is found
in other regions of the cortex.)

All of these studies confirm the heightened susceptibility of the adolescent
rodent brain to alcohol-induced inhibition of hippocampal function and memory
formation.

ADOLESCENTS ARE LESS SENSITIVE THAN ADULTS TO OTHER ALCOHOL EFFECTS

As the preceding section has shown, adolescent animals are uniquely sensitive
to some of alcohol’s effects on memory. However, adolescents seem
less sensitive than adults to other effects of drinking, such as impairment
of motor coordination, sedation, and susceptibility to seizures during withdrawal.

Motor Coordination

One of the most obvious effects of alcohol consumption in humans as well
as laboratory animals is the impairment of motor activity and coordination.
Alcohol interferes with a person’s ability to perform tasks that require
balance and motor coordination, such as standing still, walking in a straight
line, or driving an automobile. In animals, alcohol’s effects on motor
coordination can be demonstrated using the tilting plane test, in which
an animal is placed on a horizontal platform that is gradually tilted, so
that the animal must adjust its position to maintain its balance.

Motor coordination is one of the primary functions of the cerebellum,
an area at the base of the brain. Because the cerebellum continues to develop
during adolescence, it is reasonable to assume that alcohol might affect
motor coordination in adolescents differently than in adults. To investigate
this possibility, White and colleagues (2002a) analyzed the motor coordination
of adolescent and adult rats using the tilting plane test before, and at
various time points after, administering alcohol at three different doses
(1.0, 2.0, and 3.0 g/kg body weight). These researchers found that the lowest
alcohol dose did not affect the animals’ performance in either age
group. At almost all time points after the administration of the two higher
doses, however, the adult animals were more impaired than the adolescent
animals. These findings clearly demonstrate that, in contrast to alcohol’s
effects on memory, adolescent rats appear to be less sensitive to alcohol’s
effects on motor coordination than adult rats. It is not clear precisely
why the adolescent animals were less sensitive to alcohol-induced motor
impairment. It is clear, however, that the cerebellum, which plays a critical
role in motor coordination, still is developing quite rapidly during adolescence.
If the cerebellum is less sensitive to alcohol during this period, this
could account for the developmental difference in sensitivity to alcohol.
Currently, it is not known if this difference in sensitivity also applies
to human adolescents.

Sedation

Another common effect of alcohol consumption that can be observed both
in humans and in animals is sedation. With increasing alcohol consumption,
drinkers tend to become sleepy and eventually may even pass out. In laboratory
animals, sedation can be assessed by observing the righting reflex that
normally helps the animals get back on all four feet if they fall over.
When treated with sedative agents, animals temporarily lose this righting
reflex, and the duration of this loss is a measure of the sedative potency
of an agent.

To better characterize alcohol’s effects on the developing organism,
researchers also have evaluated alcohol’s sedative effects in rats
of different ages. Little and colleagues (1996) injected animals from three
age groups—juvenile animals (PD20), adolescent animals (PD30), and
adult animals (PD60)—with three different alcohol doses, and found
the following:

When treated with the lowest alcohol dose (3 g/kg body weight), none
of the adolescent animals lost their righting reflex, whereas one-half
of the juvenile rats and two-thirds of the adult rats did.

Adolescent animals lost the righting reflex for a significantly shorter
period of time than adult animals. When they regained the reflex, adolescent
animals also had significantly higher blood alcohol concentrations than
the adult animals had when they regained the righting reflex.

The juvenile animals also lost the righting reflex for a significantly
shorter time than the adult animals, although not as short as the adolescent
animals.

These observations demonstrate that, as with alcohol’s motor-impairing
effects, adolescent animals are substantially less sensitive to alcohol’s
sedative effects. Mechanisms that may contribute to this lower sensitivity
are discussed in the following section.

Mechanisms That May Contribute to Reduced Motor-Impairing
and Sedative Effects in Adolescents

Researchers have not yet identified the mechanisms that account for the
fact that adolescents are less susceptible to alcohol-related motor impairment
and sedation than older individuals. It is likely, however, that the neurotransmitter
GABA and its receptors play a role in both of these effects. As mentioned
earlier, GABA is an inhibitory neurotransmitter, and the activity of GABA
and its receptors is enhanced by alcohol. As a result, the GABA system has
been implicated in both alcohol’s sedative and its motor-impairing
effects. Studies using rats have found that the levels of GABA receptors
in various brain structures, including the cerebellum, increase markedly
throughout adolescence and reach their final levels during early adulthood
(Moy et al. 1998). Thus, it appears possible that adolescent rats are less
sensitive to alcohol-induced motor impairment and sedation because, compared
with older animals, they have fewer GABA receptors on which alcohol can
act. Another possibility is that the function of GABA receptors is altered
across adolescent development in a way that results in increased sensitivity
to alcohol as the animal gets older.

The combination of reduced sensitivity to alcohol’s motor-impairing
and sedative effects on the one hand and increased sensitivity to alcohol’s
memory-impairing effects on the other hand could be particularly harmful
to adolescents. For most people, the maximum amount of alcohol they can
consume is determined by alcohol’s motor-impairing and sedative effects—that
is, if they do not stop drinking voluntarily, drinkers at some point become
so incapacitated that they cannot continue to drink even if they want to.
If, like adolescent animals, human adolescents also are less sensitive to
these alcohol effects, it appears plausible that they might continue to
drink longer than adults, achieving higher blood alcohol concentrations
in the process. As a result, the adolescents could become even more vulnerable
to the effects of alcohol on memory and other functions to which they are
more susceptible than adults even at lower blood alcohol levels.

Susceptibility to Seizures During Withdrawal

Like all neurotransmitters, GABA has numerous functions and effects in
regulating brain activity. For example, in addition to playing a role in
motor impairment and sedation, GABA also is involved in the development
of seizures during alcohol withdrawal. Long-term drinking causes the body
to adjust to the continued presence of alcohol so that it eventually functions
normally only in the presence of the drug. At that point, cessation of drinking
can lead to an array of adverse symptoms, collectively called withdrawal,
which include symptoms mediated by GABA.

Because alcohol stimulates the activity of GABA receptors, long-term drinking
causes the brain to produce fewer of these receptors. If alcohol then is
withheld, GABA activity suddenly drops off because fewer GABA receptors
are available and alcohol no longer activates the ones that remain. This
insufficient GABA activity has been linked to the development of seizures
during withdrawal. If adolescents are less sensitive than adults to alcohol’s
effects on GABA and its receptors, adolescents also should be less prone
to seizures during withdrawal from alcohol.

This hypothesis has been investigated in rats. For these experiments,
Acheson and colleagues (1999) administered alcohol to adolescent and adult
rats for 5 days, then injected the animals with a chemical that induces
seizures and rated the severity and duration of the seizures. The study
found that although adolescent and adult animals experienced seizures of
various severities at a similar rate, the more severe seizures lasted significantly
longer in the adult animals than in the adolescent animals. Thus, this study
supports the hypothesis that adolescent animals are less sensitive than
adults to alcohol’s effects on the GABA system.

When investigating alcohol’s effects on the adolescent brain, it
is important not only to focus on the immediate effects (e.g., memory impairment,
motor impairment, or sedation) but also to explore the consequences of alcohol
use on the adolescent’s future development. Because the brain undergoes
such extensive changes and remodeling during adolescence, it is reasonable
to assume that disruption of these processes by alcohol could lead to long-term
alterations that influence adult behavior and responses to alcohol.

The preceding sections have described how acute alcohol exposure affects
the body differently during adolescence than during adulthood, with adolescents
being more sensitive to some effects of alcohol and less sensitive to others.
In addition, adolescents may respond differently to repeated heavy alcohol
exposure, a drinking pattern also known as chronic intermittent exposure
or binge drinking, which is particularly common among adolescents. Binge
drinking is characterized by repeated episodes of heavy drinking followed
by withdrawal. Several lines of evidence suggest that these repeated withdrawal
episodes contribute to many of the effects of chronic alcohol exposure on
the brain (see White and Swartzwelder 2004).

In one study of the long-term consequences of binge drinking during adolescence,
White and colleagues (2002b) studied animals that were repeatedly
exposed to high levels of alcohol during adolescence. The alcohol-exposed
and control animals were evaluated as adults with respect to alcohol’s
effects on motor activity, using the tilted plane test. As mentioned earlier,
adult rats normally are more sensitive than adolescents to alcohol-induced
motor impairment (i.e., the rats’ sensitivity to motor impairment
increases between adolescence and adulthood). This study found, however,
that rats repeatedly exposed to alcohol during adolescence did not show
this increase in sensitivity to alcohol’s effects (White et al. 2002b);
these animals performed as well on the tilted plane test in adulthood as
they had in adolescence. In a control experiment, adult rats were exposed
to the same regimen of alcohol administration as were the adolescent animals.
When these adult rats were subsequently tested, their sensitivity to alcohol-induced
motor impairment was unchanged despite the repeated alcohol exposure. Thus,
it is not the alcohol treatment per se that leads to reduced sensitivity
to motor impairment; instead, it appears that alcohol exposure during adolescence
interferes with the developmental processes that lead to adult sensitivity
to alcohol’s effects on motor coordination.

In a similar experiment, White and colleagues (2000) evaluated how chronic
intermittent alcohol exposure during adolescence affects rats’ spatial
memory in adulthood. As discussed earlier, acute alcohol administration
impairs learning and memory more in adolescent animals than it does in adults.
For this experiment, adolescent and adult animals were repeatedly exposed
to high doses of alcohol. When all the animals had reached adulthood, the
investigators compared their ability to learn where to retrieve food in
a maze with that of animals which had never received alcohol. They found
that animals in all test groups (i.e., with or without alcohol administration
during adolescence or adulthood) learned to perform the memory task equally
well. However, when the animals received a low dose of alcohol just before
being tested on the memory task, those that had been exposed to alcohol
as adolescents performed worse than animals in the other three groups (White
et al. 2000). These results indicate that repeated alcohol exposure during
adolescence enhances the individual’s sensitivity to alcohol’s
memory-impairing effects during adulthood. Similar results were obtained
in a study of college students, which found that students with a history
of binge drinking performed worse on memory tasks after consuming alcohol
than did students without such a history (Weissenborn and Duka 2003).

Researchers also have demonstrated the long-term consequences of adolescent
alcohol exposure on adult brain function by measuring the electrical brain
activity of adult rats that had or had not been repeatedly exposed to alcohol
during adolescence. Using electrodes implanted in various regions of the
animals’ brains, researchers examined both the electroencephalogram
(EEG), which is a measure of ongoing brain activity, and event-related potentials
(ERPs), which are spikes in brain activity induced by a sudden stimulus
(e.g., a light or sound). One of the studies found that animals which had
been exposed to alcohol during adolescence showed changes in the EEG pattern
as well as in ERPs measured in various brain regions, particularly the hippocampus
(Slawecki et al. 2001). These investigators noted that although similar
effects have been reported following long-term alcohol exposure during adulthood,
alcohol exposure during adolescence appears to result in more stable effects,
especially on the hippocampus, after shorter periods of exposure than would
be observed in adult animals.

Similar experiments have examined the effects of an acute alcohol dose
on the EEG of adult rats that had or had not been exposed to alcohol repeatedly
during adolescence. A study by Slawecki (2000) found that although the acute
alcohol dose significantly altered several EEG variables in the hippocampus
and other brain regions of the control animals, these variables were not
altered in the animals that had been exposed to alcohol during adolescence.
In addition, the alcohol-exposed animals showed fewer behaviors indicative
of intoxication in response to the acute alcohol dose than did the control
animals. These findings suggest that alcohol exposure during adolescence
leads to persistent and brain region–specific changes in electrical
brain activity in response to an acute alcohol dose during adulthood. In
particular, the observation that some EEG responses to alcohol were reduced
in the alcohol-exposed animals indicates that adolescent alcohol exposure
can produce long-lasting changes in responsiveness to at least some alcohol
effects.

CONCLUSIONS

Various avenues of research have demonstrated that at least in laboratory
animals, adolescence is a unique stage of brain development which is particularly
sensitive to the disrupting effects of alcohol. For example, in rodents,
adolescent alcohol exposure increases the brain’s sensitivity to some
alcohol effects (e.g., memory impairment) and decreases sensitivity to other
effects (e.g., motor impairment and sedation). Furthermore, in rodents,
alcohol exposure during adolescence not only has an immediate impact on
brain function, it also may lead to consequences for various brain functions
that last even into adulthood. To what extent these findings are applicable
to humans is a matter of debate, particularly because of the differences
between humans and rodents in terms of the plasticity and time course of
brain development. Nevertheless these findings suggest that similar processes
might occur in humans—a conclusion that is especially pertinent and
worrisome because adolescence in humans often is the period when alcohol
consumption begins and when particularly dangerous drinking patterns, such
as binge drinking, are common. This combination of frequent high alcohol
consumption and increased vulnerability of the brain to alcohol’s
harmful effects may result in cognitive deficits and other problems that
persist far beyond adolescence.

One brain area that seems to be particularly affected by adolescent alcohol
consumption is the hippocampus, which plays a role in numerous cognitive
functions, including learning and memory. In fact, preliminary studies in
humans have found that alcohol abuse during adolescence may be associated
with a reduction in the size of the hippocampus (De Bellis et al. 2000),
which in turn could be a sign of impaired hippocampal function. Theoretically,
alcohol could lead to cell death in the hippocampus through several mechanisms
(e.g., by excessive activation of the glutamate/NMDA receptor system). Several
studies, however, have failed to detect obvious nerve cell loss after repeated
exposure to various patterns of alcohol administration during adolescence
or early adulthood (see White and Swartzwelder 2004). Other studies, in
contrast, have found that high-dose binge exposure to alcohol led to brain
damage in adolescents but not in adults (Crews et al. 2000). These differences
in findings may be accounted for by differences in the rodent strain used;
in the pattern, dose, and route of alcohol administration; and in the brain
regions studied. In addition, the long-term behavioral changes that follow
chronic intermittent alcohol exposure during adolescence may involve subtle
changes in neuronal connections which are not easily measurable. Thus, additional
research is necessary to elucidate the exact effects of alcohol on the adolescent
hippocampus and other brain structures and to better understand the long-term
implications of adolescent alcohol exposure.